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    Clinical Trial Results:
    A Phase 3, Multicenter, Randomized, Double-blind, Placebo-controlled Trial of the Safety and Efficacy of Fixed-dose Brexpiprazole (OPC-34712) as Adjunctive Therapy in the Treatment of Adults with Major Depressive Disorder With and Without Anxious Distress

    Summary
    EudraCT number
    		 2014-000062-22
    Trial protocol
    		 DE   SK   HU   PL  
    Global end of trial date
    20 May 2016

    Results information
    Results version number
    		 v1(current)
    This version publication date
    13 Jul 2017
    First version publication date
    13 Jul 2017
    Other versions

    Trial information

    		 Close Top of page
    Trial identification
    Sponsor protocol code
    331-13-214
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT02196506
    WHO universal trial number (UTN)
    		 -
    Other trial identifiers
    		 IND: 103,958
    Sponsors
    Sponsor organisation name
    Otsuka Pharmaceutical Development & Commercialization, Inc
    Sponsor organisation address
    2440 Research Boulevard, Rockville, United States, MD 20850
    Public contact
    Otsuka Transparency Department, Otsuka Pharmaceutical Development & Commercialization, Inc., DT-inquiry@otsuka.jp
    Scientific contact
    Otsuka Transparency Department, Otsuka Pharmaceutical Development & Commercialization, Inc., DT-inquiry@otsuka.jp
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    No
    Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    20 May 2016
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    01 Apr 2016
    Global end of trial reached?
    Yes
    Global end of trial date
    20 May 2016
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To compare the efficacy of brexpiprazole (2.0 mg/day) to placebo as adjunctive therapy to an assigned open-label antidepressant therapy (ADT) in subjects who demonstrate an inadequate response to a prospective 8-week trial of the same assigned open-label ADT.
    Protection of trial subjects
    In accordance with the International Conference on Harmonisation (ICH) Good Clinical Practice (GCP) Consolidated Guideline and the applicable local laws and regulatory requirements of the countries in which the trial was conducted, copies of the protocol, amendments, and informed consent form (ICF) were reviewed and approved by the governing institutional review board (IRB) or independent ethics committee (IEC) for each investigational site or country, as appropriate, prior to trial start or prior to implementation of the amendment at that site or country. This trial was conducted in compliance with the protocol, ICH GCP and applicable local laws, and regulatory requirements.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    09 Jul 2014
    Long term follow-up planned
    Yes
    Long term follow-up rationale
    		 Safety, Efficacy
    Long term follow-up duration
    		 1 Months
    Independent data monitoring committee (IDMC) involvement?
    No
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    United States: 506
    Country: Number of subjects enrolled
    Poland: 95
    Country: Number of subjects enrolled
    Slovakia: 77
    Country: Number of subjects enrolled
    Germany: 95
    Country: Number of subjects enrolled
    Hungary: 64
    Worldwide total number of subjects
    837
    EEA total number of subjects
    331
    Number of subjects enrolled per age group
    In utero
    0
    Preterm newborn - gestational age < 37 wk
    0
    Newborns (0-27 days)
    0
    Infants and toddlers (28 days-23 months)
    0
    Children (2-11 years)
    0
    Adolescents (12-17 years)
    0
    Adults (18-64 years)
    830
    From 65 to 84 years
    7
    85 years and over
    0

    Subject disposition

    		 Close Top of page
    Recruitment
    Recruitment details
    		 This trial was conducted in 837 subjects at 51 trial sites in the following 5 countries: Germany, Hungary, Poland, Slovakia, and United States (US). Total of 1144 subjects with major depressive disorder were screened for the trial, 837 enrolled into Phase A, 394 were randomized into Phase B and 322 continued treatment with placebo+ADT in Phase A+.

    Pre-assignment
    Screening details
    		 Trial consisted of a screening phase and 3 phases. In phase A (8-week single-blind prospective treatment phase) and continued treatment in phase A+ (Single-blind phase A Responder), there was single treatment group. In phase B (6-week double-blind randomization phase), there were 2 treatment groups. All Outcome Measures were assessed in phase B.

    Period 1
    Period 1 title
    Phase A
    Is this the baseline period?
    		 No
    Allocation method
    Non-randomised - controlled
    Blinding used
    		 Single blind
    Roles blinded
    		 Investigator [1]

    Arms
    Arm title
    		 ALL ADT
    Arm description
    		 Subjects meeting entrance criteria who were experiencing a major depressive episode with a HAM-D17 Total Score of greater than or equal 18 at baseline were enrolled into an 8-week Single-blind Prospective Treatment Phase (Phase A). All subjects received single-blind placebo plus an investigator determined, open-label, ADT (antidepressant therapy). Once assigned to an ADT by the investigator, subjects remained on the same ADT for the duration of the trial. At the Week 8 visit, the IWRS (Interactive web response system) determined based on scores entered by the investigator, whether a subject was a “Phase A Responder” or a “Phase A Inadequate Responder.”
    Arm type
    		 Experimental

    Investigational medicinal product name
    Escitalopram (Lexapro) tablets
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    10 or 20 mg/day, Dosed once daily at the same time each day.

    Investigational medicinal product name
    Fluoxetine (Prozac) capsules
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    20 or 40 mg/day, Fluoxetine 20 mg was dosed once daily. Fluoxetine 40 mg could be dosed once daily or in divided doses twice daily. All doses were taken at the same time each day.

    Investigational medicinal product name
    Paroxetine (Paxil CR) controlled-release (CR) tablets
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    25, 37.5 or 50 mg/day, Dosed once daily at the same time each day.

    Investigational medicinal product name
    Sertraline (Zoloft) tablets
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    50, 100, 150, or 200 mg/day, Dosed once daily at the same time each day.

    Investigational medicinal product name
    Duloxetine (Cymbalta) delayed-release capsules
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    30, 40 or 60 mg/day, Duloxetine 60 mg was administered once daily or as duloxetine 30 mg twice daily; duloxetine 40 mg was administered once daily or as duloxetine 20 mg twice daily. All doses should be taken at the same time each day.

    Investigational medicinal product name
    Venlafaxine XR (Effexor XR) extended-release (XR) capsules
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    37.5, 75, 150 or 225 mg/day, Dosed once daily at the same time each day. Subjects assigned to venlafaxine XR received 37.5 mg/day from Days 1 through 4 and 75 mg/day from Days 5 through 7 during the first week of Phase A. Venlafaxine XR was to be taken with food.

    Investigational medicinal product name
    Placebo for brexpiprazole
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    1 tablet along with ADT

    Notes
    [1] - The roles blinded appear inconsistent with a simple blinded trial.
    Justification: Phase A is a 8-week Single-blind Prospective Treatment Phase during which all subjects received single-blind placebo plus an investigator determined, open-label, ADT.
    Number of subjects in period 1
    		ALL ADT
    Started
    837
    Completed
    716
    Not completed
    121
         Consent withdrawn by subject
    34
         Subject Was Withdrawn By the investigator
    10
         Adverse Events
    22
         Subject Met Withdrawal Criteria
    34
         Lost to follow-up
    9
         Protocol deviation
    12
    Period 2
    Period 2 title
    Phase B
    Is this the baseline period?
    		 Yes [2]
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator, Carer, Assessor

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 2mg Brex+ADT
    Arm description
    		 Subjects with an inadequate response in Phase A who were negative for cocaine, marijuana, and other illicit drugs at the Week 6 visit and who, in the investigator’s judgment, were suitable for randomization, were randomized at the end of prospective treatment (Week 8 visit of Phase A) to the following double-blind treatment regimen:  Adjunctive 2 mg/day brexpiprazole-plus-ADT (2 mg/day brexpiprazole+ADT)
    Arm type
    		 Experimental

    Investigational medicinal product name
    Escitalopram (Lexapro) tablets
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    10 or 20 mg/day, Dosed once daily at the same time each day.

    Investigational medicinal product name
    Fluoxetine (Prozac) capsules
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    20 or 40 mg/day, Fluoxetine 20 mg was dosed once daily. Fluoxetine 40 mg could be dosed once daily or in divided doses twice daily. All doses were taken at the same time each day.

    Investigational medicinal product name
    Paroxetine (Paxil CR) controlled-release (CR) tablets
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    25, 37.5 or 50 mg/day, Dosed once daily at the same time each day.

    Investigational medicinal product name
    Sertraline (Zoloft) tablets
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    50, 100, 150, or 200 mg/day, Dosed once daily at the same time each day.

    Investigational medicinal product name
    Duloxetine (Cymbalta) delayed-release capsules
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    30, 40 or 60 mg/day, Duloxetine 60 mg was administered once daily or as duloxetine 30 mg twice daily; duloxetine 40 mg was administered once daily or as duloxetine 20 mg twice daily. All doses should be taken at the same time each day.

    Investigational medicinal product name
    Venlafaxine XR (Effexor XR) extended-release (XR) capsules
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    37.5, 75, 150 or 225 mg/day, Dosed once daily at the same time each day. Subjects assigned to venlafaxine XR received 37.5 mg/day from Days 1 through 4 and 75 mg/day from Days 5 through 7 during the first week of Phase A. Venlafaxine XR was to be taken with food.

    Investigational medicinal product name
    Brexpiprazole 2.0 mg/day
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    0.5 mg/day in week 8, 1 mg/day in week 9, 2.0 mg/day from week 10 to week 13.

    Arm title
    		 Placebo+ADT
    Arm description
    		 Subjects with an inadequate response in Phase A who were negative for cocaine, marijuana, and other illicit drugs at the Week 6 visit and who, in the investigator’s judgment, were suitable for randomization, were randomized at the end of prospective treatment (Week 8 visit of Phase A) to the following double-blind treatment regimen:   Continued placebo-plus-ADT (placebo+ADT)
    Arm type
    		 Placebo

    Investigational medicinal product name
    Escitalopram (Lexapro) tablets
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    10 or 20 mg/day, Dosed once daily at the same time each day.

    Investigational medicinal product name
    Fluoxetine (Prozac) capsules
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    20 or 40 mg/day, Fluoxetine 20 mg was dosed once daily. Fluoxetine 40 mg could be dosed once daily or in divided doses twice daily. All doses were taken at the same time each day.

    Investigational medicinal product name
    Paroxetine (Paxil CR) controlled-release (CR) tablets
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    25, 37.5 or 50 mg/day, Dosed once daily at the same time each day.

    Investigational medicinal product name
    Sertraline (Zoloft) tablets
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    50, 100, 150, or 200 mg/day, Dosed once daily at the same time each day.

    Investigational medicinal product name
    Duloxetine (Cymbalta) delayed-release capsules
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    30, 40 or 60 mg/day, Duloxetine 60 mg was administered once daily or as duloxetine 30 mg twice daily; duloxetine 40 mg was administered once daily or as duloxetine 20 mg twice daily. All doses should be taken at the same time each day.

    Investigational medicinal product name
    Venlafaxine XR (Effexor XR) extended-release (XR) capsules
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    37.5, 75, 150 or 225 mg/day, Dosed once daily at the same time each day. Subjects assigned to venlafaxine XR received 37.5 mg/day from Days 1 through 4 and 75 mg/day from Days 5 through 7 during the first week of Phase A. Venlafaxine XR was to be taken with food.

    Investigational medicinal product name
    Placebo for brexpiprazole
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    1 tablet along with ADT

    Notes
    [2] - Period 1 is not the baseline period. It is expected that period 1 will be the baseline period.
    Justification: Period 2 (Phase B) is the baseline period for this study.
    Number of subjects in period 2 [3] [4]
    		2mg Brex+ADT Placebo+ADT
    Started
    192
    202
    Completed
    177
    196
    Not completed
    15
    6
         Consent withdrawn by subject
    8
    1
         Adverse Events
    4
    1
         Lost to follow-up
    2
    1
         Subject Met Withdrawal Criteria
    -
    1
         Lack of efficacy
    1
    2
    Notes
    [3] - The number of subjects reported to be in the baseline period are not the same as the worldwide number enrolled in the trial. It is expected that these numbers will be the same.
    Justification: Period 2 (Phase B) is the baseline period for this study. A total of 1144 subjects were screened for this trial and 837 subjects enrolled into Phase A. Of these subjects, 121 subjects (14.5%) discontinued the trial during Phase A, 394 subjects (47.1%) were subsequently randomized to double-blind IMP in Phase B (192 subjects randomized to 2 mg/day brexpiprazole+ADT and 202 randomized to placebo+ADT), and 322 subjects (38.5%) continued placebo+ADT in Phase A+.
    [4] - The number of subjects starting the period is not consistent with the number completing the preceding period. It is expected the number of subjects starting the subsequent period will be the same as the number completing the preceding period.
    Justification: A total of 1144 subjects were screened for this trial and 837 subjects enrolled into Phase A. A total of 837 subjects received at least 1 dose of ADT during Phase A. Of these subjects, 121 subjects (14.5%) discontinued the trial during Phase A, 394 subjects (47.1%) were subsequently randomized to double-blind IMP in Phase B (192 subjects randomized to 2 mg/day brexpiprazole+ADT and 202 randomized to placebo+ADT), and 322 subjects (38.5%) continued placebo+ADT in Phase A+.
    Period 3
    Period 3 title
    Phase A +
    Is this the baseline period?
    		 No
    Allocation method
    Non-randomised - controlled
    Blinding used
    		 Single blind
    Roles blinded
    		 Investigator [5]

    Arms
    Arm title
    		 ALL ADT
    Arm description
    		 Phase A+ included subjects who met criteria for a response at the end of the prospective treatment phase (Week 8 visit of Phase A) and subjects who were not suitable for randomization in Phase B per the judgment of the investigator or medical monitor. Treatment response in Phase A was determined at the Week 8 visit based on improvement or lack of improvement of the subject’s depressive symptoms, which was confirmed by clinical criteria that prospectively defined response. Subject response was determined from clinical data that were entered into the IWRS at each visit. Subjects in Phase A+ received single-blind placebo+ADT for an additional 6 weeks, for a total of 14 weeks, and attended visits at Weeks 11 and 14.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Escitalopram (Lexapro) tablets
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    10 or 20 mg/day, Dosed once daily at the same time each day.

    Investigational medicinal product name
    Fluoxetine (Prozac) capsules
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    20 or 40 mg/day, Fluoxetine 20 mg was dosed once daily. Fluoxetine 40 mg could be dosed once daily or in divided doses twice daily. All doses were taken at the same time each day.

    Investigational medicinal product name
    Paroxetine (Paxil CR) controlled-release (CR) tablets
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    25, 37.5 or 50 mg/day, Dosed once daily at the same time each day.

    Investigational medicinal product name
    Sertraline (Zoloft) tablets
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    50, 100, 150, or 200 mg/day, Dosed once daily at the same time each day.

    Investigational medicinal product name
    Duloxetine (Cymbalta) delayed-release capsules
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    30, 40 or 60 mg/day, Duloxetine 60 mg was administered once daily or as duloxetine 30 mg twice daily; duloxetine 40 mg was administered once daily or as duloxetine 20 mg twice daily. All doses should be taken at the same time each day.

    Investigational medicinal product name
    Venlafaxine XR (Effexor XR) extended-release (XR) capsules
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    37.5, 75, 150 or 225 mg/day, Dosed once daily at the same time each day. Subjects assigned to venlafaxine XR received 37.5 mg/day from Days 1 through 4 and 75 mg/day from Days 5 through 7 during the first week of Phase A. Venlafaxine XR was to be taken with food.

    Investigational medicinal product name
    Placebo for brexpiprazole
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    1 tablet along with ADT

    Notes
    [5] - The roles blinded appear inconsistent with a simple blinded trial.
    Justification: Phase A+ included subjects who met criteria for a response at the end of the prospective treatment phase (Week 8 visit of Phase A) and subjects who were not suitable for randomization in Phase B per the judgment of the investigator or medical monitor. Subjects in Phase A+ received single-blind placebo+ADT for an additional 6 weeks, for a total of 14 weeks.
    Number of subjects in period 3 [6]
    		ALL ADT
    Started
    322
    Completed
    308
    Not completed
    14
         Consent withdrawn by subject
    5
         Subject Was Withdrawn By the investigator
    1
         Adverse Events
    1
         Lost to follow-up
    6
         Subject Met Withdrawal Criteria
    1
    Notes
    [6] - The number of subjects starting the period is not consistent with the number completing the preceding period. It is expected the number of subjects starting the subsequent period will be the same as the number completing the preceding period.
    Justification: A total of 1144 subjects were screened for this trial and 837 subjects enrolled into Phase A. A total of 837 subjects received at least 1 dose of ADT during Phase A. Of these subjects, 121 subjects (14.5%) discontinued the trial during Phase A, 394 subjects (47.1%) were subsequently randomized to double-blind IMP in Phase B (192 subjects randomized to 2 mg/day brexpiprazole+ADT and 202 randomized to placebo+ADT), and 322 subjects (38.5%) continued placebo+ADT in Phase A+.

    Baseline characteristics

    		 Close Top of page
    Baseline characteristics reporting groups
    Reporting group title
    2mg Brex+ADT
    Reporting group description
    		 Subjects with an inadequate response in Phase A who were negative for cocaine, marijuana, and other illicit drugs at the Week 6 visit and who, in the investigator’s judgment, were suitable for randomization, were randomized at the end of prospective treatment (Week 8 visit of Phase A) to the following double-blind treatment regimen:  Adjunctive 2 mg/day brexpiprazole-plus-ADT (2 mg/day brexpiprazole+ADT)

    Reporting group title
    Placebo+ADT
    Reporting group description
    		 Subjects with an inadequate response in Phase A who were negative for cocaine, marijuana, and other illicit drugs at the Week 6 visit and who, in the investigator’s judgment, were suitable for randomization, were randomized at the end of prospective treatment (Week 8 visit of Phase A) to the following double-blind treatment regimen:   Continued placebo-plus-ADT (placebo+ADT)

    Reporting group values
    		 2mg Brex+ADT Placebo+ADT Total
    Number of subjects
    		 192 202 394
    Age categorical
    Baseline measures are based on the subjects from the Double-blind Placebo-controlled Phase
    Units: Subjects
        In utero
    		 0 0 0
        Preterm newborn infants (gestational age < 37 wks)
    		 0 0 0
        Newborns (0-27 days)
    		 0 0 0
        Infants and toddlers (28 days-23 months)
    		 0 0 0
        Children (2-11 years)
    		 0 0 0
        Adolescents (12-17 years)
    		 0 0 0
        Adults (18-64 years)
    		 192 200 392
        From 65-84 years
    		 0 2 2
        85 years and over
    		 0 0 0
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 43 ± 12.7 42.7 ± 12.5 -
    Gender categorical
    Units: Subjects
        Female
    		 147 144 291
        Male
    		 45 58 103
    Type of Episode [n (%)]
    Units: Subjects
        Single Episode
    		 32 35 67
        Recurrent Episode
    		 160 167 327
    Duration of Current Episode (Months)
    Units: Months
        arithmetic mean (standard deviation)
    		 13.3 ± 14.2 19.4 ± 46.8 -
    Number of Lifetime Episodes
    Units: Number
        arithmetic mean (standard deviation)
    		 3.1 ± 1.8 3.2 ± 2.4 -

    End points

    		 Close Top of page
    End points reporting groups
    Reporting group title
    ALL ADT
    Reporting group description
    		 Subjects meeting entrance criteria who were experiencing a major depressive episode with a HAM-D17 Total Score of greater than or equal 18 at baseline were enrolled into an 8-week Single-blind Prospective Treatment Phase (Phase A). All subjects received single-blind placebo plus an investigator determined, open-label, ADT (antidepressant therapy). Once assigned to an ADT by the investigator, subjects remained on the same ADT for the duration of the trial. At the Week 8 visit, the IWRS (Interactive web response system) determined based on scores entered by the investigator, whether a subject was a “Phase A Responder” or a “Phase A Inadequate Responder.”
    Reporting group title
    2mg Brex+ADT
    Reporting group description
    		 Subjects with an inadequate response in Phase A who were negative for cocaine, marijuana, and other illicit drugs at the Week 6 visit and who, in the investigator’s judgment, were suitable for randomization, were randomized at the end of prospective treatment (Week 8 visit of Phase A) to the following double-blind treatment regimen:  Adjunctive 2 mg/day brexpiprazole-plus-ADT (2 mg/day brexpiprazole+ADT)

    Reporting group title
    Placebo+ADT
    Reporting group description
    		 Subjects with an inadequate response in Phase A who were negative for cocaine, marijuana, and other illicit drugs at the Week 6 visit and who, in the investigator’s judgment, were suitable for randomization, were randomized at the end of prospective treatment (Week 8 visit of Phase A) to the following double-blind treatment regimen:   Continued placebo-plus-ADT (placebo+ADT)
    Reporting group title
    ALL ADT
    Reporting group description
    		 Phase A+ included subjects who met criteria for a response at the end of the prospective treatment phase (Week 8 visit of Phase A) and subjects who were not suitable for randomization in Phase B per the judgment of the investigator or medical monitor. Treatment response in Phase A was determined at the Week 8 visit based on improvement or lack of improvement of the subject’s depressive symptoms, which was confirmed by clinical criteria that prospectively defined response. Subject response was determined from clinical data that were entered into the IWRS at each visit. Subjects in Phase A+ received single-blind placebo+ADT for an additional 6 weeks, for a total of 14 weeks, and attended visits at Weeks 11 and 14.

    Primary: Change from the end of Phase A (Week 8 visit) to the end of Phase B (Week 14 visit) in the Montgomery Asberg Depression Rating Scale (MADRS) Total Score

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    End point title
    		 Change from the end of Phase A (Week 8 visit) to the end of Phase B (Week 14 visit) in the Montgomery Asberg Depression Rating Scale (MADRS) Total Score
    End point description
    The MADRS was utilized as the primary efficacy assessment of the subject’s level of depression and was administered utilizing the Structured Interview Guide for the MADRS (SIGMA). Detailed instructions for administration of this structured interview was provided in the SIGMA. The MADRS consisted of 10 items each with 7 defined grades of severity. The rating was based on a clinical interview moving from broadly phrased questions about symptoms to more detailed ones which allowed a precise rating of severity. The rater decided whether the rating lied on predefined scale steps (0, 2, 4, 6) or between them (1, 3, 5). The 10 items were Apparent sadness, Reported sadness, Inner tension, Reduced sleep, Reduced appetite, Concentration difficulties, Lassitude, Inability to feel, Pessimistic thoughts, Suicidal thoughts.
    End point type
    Primary
    End point timeframe
    From baseline (end of Phase A [Week 8]) to Week 14
    End point values
    		 2mg Brex+ADT Placebo+ADT
    Number of subjects analysed
    191
    202
    Units: Participants
        least squares mean (standard error)
    -10.4 ± 0.63
    -8.07 ± 0.61
    Statistical analysis title
    		 Statistical analysis At Week 14
    Comparison groups
    2mg Brex+ADT v Placebo+ADT
    Number of subjects included in analysis
    393
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0074 [1]
    Method
    		 Mixed models analysis
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -2.3
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -3.97
         upper limit
    		 -0.62
    Notes
    [1] - Comparison between treatment groups was carried out using MMRM (Mixed-model repeated measures), with trial site, treatment group, visit, and treatment group-by-visit interaction as factor and baseline-by-visit interaction as a covariate.

    Secondary: Change from Baseline (end of Phase A [Week 8 visit] to end of Phase B (Week 14 visit) in Sheehan Disability Scale (SDS) Mean Score for the Efficacy Sample

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    End point title
    		 Change from Baseline (end of Phase A [Week 8 visit] to end of Phase B (Week 14 visit) in Sheehan Disability Scale (SDS) Mean Score for the Efficacy Sample
    End point description
    The SDS was a self-rated instrument used to measure the effect of the subject’s symptoms on work/school, social life, and family/home responsibilities. The SDS was a visual analogue scale that used spatio-visual, numeric, and verbal descriptive anchors simultaneously to assess disability across the 3 domains. The number most representative of how much each area was disrupted by symptoms was marked along the line from 0 = not at all, to 10 = extremely. Scores of 5 and above were associated with significant functional impairment. In addition to the visual scale, the SDS included 2 questions related to productivity losses due to the psychiatric symptoms and impairment.
    End point type
    Secondary
    End point timeframe
    From baseline (end of Phase A [Week 8]) to Week 14
    End point values
    		 2mg Brex+ADT Placebo+ADT
    Number of subjects analysed
    187
    200
    Units: Participants
        least squares mean (standard error)
    -1.63 ± 0.18
    -1.41 ± 0.17
    Statistical analysis title
    		 Statistical Analysis for Change At Week 14
    Comparison groups
    2mg Brex+ADT v Placebo+ADT
    Number of subjects included in analysis
    387
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.3331 [2]
    Method
    		 Mixed models analysis
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -0.22
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.66
         upper limit
    		 0.23
    Notes
    [2] - Comparison between treatment groups was carried out using MMRM, with trial site, treatment group, visit, and treatment.group-by-visit interaction as factor and baseline-by-visit interaction as a covariate. An "unstructured" covariance was used.

    Secondary: Change from Baseline (End of Phase A [Week 8 visit] to end of Phase B (Week 14 visit) in MADRS Total Score for the subpopulation with < 25% improvement from baseline of Phase A (Week 0) to end of Phase A (Week 8) in MADRS Total Score

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    End point title
    		 Change from Baseline (End of Phase A [Week 8 visit] to end of Phase B (Week 14 visit) in MADRS Total Score for the subpopulation with < 25% improvement from baseline of Phase A (Week 0) to end of Phase A (Week 8) in MADRS Total Score
    End point description
    The MADRS was utilized as the efficacy assessment of the subject’s level of depression and was administered utilizing the Structured Interview Guide for the MADRS (SIGMA). Detailed instructions for administration of this structured interview was provided in the SIGMA. The MADRS consisted of 10 items each with 7 defined grades of severity.
    End point type
    Secondary
    End point timeframe
    From baseline (end of Phase A [Week 8]) to Week 14
    End point values
    		 2mg Brex+ADT Placebo+ADT
    Number of subjects analysed
    161
    158
    Units: Participants
        least squares mean (standard error)
    -11.1 ± 0.71
    -8.87 ± 0.71
    Statistical analysis title
    		 Statistical Analysis At Week 14
    Comparison groups
    2mg Brex+ADT v Placebo+ADT
    Number of subjects included in analysis
    319
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0263 [3]
    Method
    		 Mixed models analysis
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -2.25
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -4.23
         upper limit
    		 -0.27
    Notes
    [3] - Comparison between treatment groups was carried out using MMRM, with treatment group, visit, and treatment group-by-visit interaction as factor and baseline-by-visit interaction as a covariate. An "unstructured" covariance was used.

    Secondary: Change from Baseline (End of Phase A [Week 8]) to end of Phase B (Week 14 visit) in MADRS Total Score for the subpopulation with anxious distress as specified in DSM-V.

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    End point title
    		 Change from Baseline (End of Phase A [Week 8]) to end of Phase B (Week 14 visit) in MADRS Total Score for the subpopulation with anxious distress as specified in DSM-V.
    End point description
    To assess the change From End of Phase A to End of Phase B in MADRS Total Score for the Subpopulations With Anxious Distress as Specified in Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-V).
    End point type
    Secondary
    End point timeframe
    From baseline (end of Phase A [Week 8]) to Week 14
    End point values
    		 2mg Brex+ADT Placebo+ADT
    Number of subjects analysed
    124
    124
    Units: Participants
        least squares mean (standard error)
    -11.8 ± 0.81
    -8.87 ± 0.81
    Statistical analysis title
    		 Statistical Analysis At Week 14
    Comparison groups
    2mg Brex+ADT v Placebo+ADT
    Number of subjects included in analysis
    248
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0099 [4]
    Method
    		 Mixed models analysis
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -2.98
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -5.24
         upper limit
    		 -0.72
    Notes
    [4] - Comparison between treatment groups was carried out using MMRM, with treatment group, visit, and treatment group-by-visit interaction as factor and baseline-by-visit interaction as a covariate. An "unstructured" covariance was used.

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Adverse events were recorded throughout the trial.
    Assessment type
    		 Non-systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    19.1
    Reporting groups
    Reporting group title
    2mg Brex+ADT
    Reporting group description
    		 Subjects with an inadequate response in Phase A who were negative for cocaine, marijuana, and other illicit drugs at the Week 6 visit and who, in the investigator’s judgment, were suitable for randomization, were randomized at the end of prospective treatment (Week 8 visit of Phase A) to the following double-blind treatment regimen:  Adjunctive 2 mg/day brexpiprazole-plus-ADT (2 mg/day brexpiprazole+ADT)

    Reporting group title
    Placebo+ADT
    Reporting group description
    		 Subjects with an inadequate response in Phase A who were negative for cocaine, marijuana, and other illicit drugs at the Week 6 visit and who, in the investigator’s judgment, were suitable for randomization, were randomized at the end of prospective treatment (Week 8 visit of Phase A) to the following double-blind treatment regimen:   Continued placebo-plus-ADT (placebo+ADT)

    Serious adverse events
    		 2mg Brex+ADT Placebo+ADT
    Total subjects affected by serious adverse events
         subjects affected / exposed
    1 / 192 (0.52%)
    0 / 202 (0.00%)
         number of deaths (all causes)
    0
    0
         number of deaths resulting from adverse events
    0
    0
    Ear and labyrinth disorders
    Vertigo
         subjects affected / exposed
    1 / 192 (0.52%)
    0 / 202 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 2mg Brex+ADT Placebo+ADT
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    49 / 192 (25.52%)
    35 / 202 (17.33%)
    Investigations
    Weight increased
         subjects affected / exposed
    10 / 192 (5.21%)
    1 / 202 (0.50%)
         occurrences all number
    10
    1
    Nervous system disorders
    Akathisia
         subjects affected / exposed
    16 / 192 (8.33%)
    10 / 202 (4.95%)
         occurrences all number
    17
    12
    Headache
         subjects affected / exposed
    7 / 192 (3.65%)
    15 / 202 (7.43%)
         occurrences all number
    7
    24
    Psychiatric disorders
    Restlessness
         subjects affected / exposed
    16 / 192 (8.33%)
    4 / 202 (1.98%)
         occurrences all number
    16
    4
    Infections and infestations
    Upper respiratory tract infection
         subjects affected / exposed
    10 / 192 (5.21%)
    10 / 202 (4.95%)
         occurrences all number
    11
    11

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    17 Jun 2014
    Amendment 1: Updated the title of the study to include one of the prespecified populations and changing the Director of Clinical Management. Added additional analyses for prespecified populations; specifically:  Subjects who showed minimal improvement in Phase A of the trial (< 25% improvement from baseline of Phase A [Week 0] to end of Phase A [Week 8 visit] on MADRS Total Score).  Subjects with anxious distress as specified in DSM-V.
    15 Aug 2014
    Amendment 2: Changes were made to text because rollover to the open-label extension trial following participation in this trial was no longer available to subjects. The open-label extension trial was no longer allowing subjects to rollover because it had already exceeded the requirement for long-term exposure as defined by the International Conference on Harmonisation guidance (ICH E1A).

    Interruptions (globally)
    Were there any global interruptions to the trial? No

    Limitations and caveats
    Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.
    None reported
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